Lynn Zechiedrich Ph.D.
DNA Topoisomerases and Antibiotic Resistance in E. coli
-
- Associate Professor
- Ph.D.
Vanderbilt University - Postdoc
University of California, Berkeley - 713-798-5126
- elz@bcm.edu
By passing DNA strands through each other, the ubiquitous topoisomerases control chromosome condensation, chromosome segregation, replication, transcription, and recombination. The topoisomerases break and reseal DNA to modulate DNA supercoils, DNA catenanes, and DNA knots (single lines represent the double helix in the drawing). Although each of the four topoisomerases in E. coli are able, under certain biochemical conditions, to modulate all three topological forms of DNA, we have found that each topoisomerase has a unique role in the cell.
We are using genetic and biochemical techniques to determine how each topoisomerase carries out its specific role and how supercoils, catenanes, and knots affect the cell. Because of their essential roles, bacterial topoisomerases are the cellular targets for some of the most active, broad-spectrum oral antibiotics, the quinolones. These drugs kill by the same mechanism as several classes of anti-topoisomerase drugs used in the treatment of human cancer. The normally short-lived, broken DNA intermediate produced by topoisomerases is increased by the drugs, which causes cell death.
Current projects in the laboratory include determining how cells resist quinolones. We have identified approximately 20 new genes that are important for quinolone resistance in E. coli. Some of these genes affect multidrug resistance. Results from our research will further the understanding of topoisomerase mechanisms, DNA structure, and toxicity of anti-topoisomerase drugs. Our work may allow us to better fight the worldwide problem of drug resistance.